Our principal hypothesis is that secretion of the intestinal hormone, Cholecystokinin (CCK), as mediated by luminal CK-releasing factor (LCRF). Emerging evidence how indicates that mechanisms underlying stimulation of intestinal peptide hormone secretion involve luminal endocrine-like releasing factors. The long sought after luminal releasing factor for cholecystokinin (CCK) or Luminal Cholecystokinin Releasing Factor (LCRF) has recently been isolated. Our laboratory has shown that LCRF is expected primarily in the intestinal epithelium Brunner's glands and pancreatic ductules. We have measured secretion of LCRF into the intestinal lumen by radioimmunoassay. We propose that luminal nutrients provoke LCRF release from the intestinal epithelium. Brunner's glands and pancreatic ductules into the lumen; luminal LCRF than triggers intestinal CK secretion. We also have preliminary data to show the existence of large species of LCRF in the intestinal epithelial and lumen, and that a peptide hormone processing enzyme, pro-hormone convertase- 5 (PC-5) is co-localized and co-secreted with LCRF into the lumen. These findings suggest that LCRF is processed before secretion and post- secretory within the intestinal lumen to a biologically active form by PC- 5. The primary objectives of this research proposal are to characterize the biological activity of LCRF on CCK secretion, and to test the hypothesis that luminal LCRF regulates intestinal CCK secretion. The Specific Aims of this research proposal are; 1) to characterize the biological activity of LCRF on CCK secretion; and, 2) to demonstrate that LCRF mediates physiologically relevant intestinal CK secretion. Accomplishment of our proposed aims will result in fundamental new knowledge regarding the role of LCRF in the regulation of CCK secretion and its potential for therapeutic applications in digestive diseases, including pancreatitis, gallstone diseases, motility and eating disorders. LCRF appears to represent a unique model of endocrine peptide secretion and processing since LCRF may be the first described lumone. Lumones are hormone- like factors produced by intestinal cells, secreted into the intestinal lumen and delivered to their target cells residing in the intestinal epithelium. The intestinal lumen may be an important pathway for endocrine secretion and action and regulation of gastrointestinal function.